New MAB with Unique Site of Action Investigated for Uncontrolled Asthma

The investigational monoclonal antibody (MAB), tezepelumab (MedImmune and Amgen) evidenced efficacy in a dose-comparison trial for adults with uncontrolled asthma, including in those without eosinophilia who can be less responsive to available treatments.

Jonathan Corren (pictured), MD, an allergist-immunologist in the department of medicine at UCLA, and colleagues reported results from the year-long phase 2 double-blind, placebo-controlled trial of 3 doses of tezepelumab, suggesting its mechanism of action could be advantageous to patients with or without eosinophilic inflammation.

Tezepelumab binds to thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, preventing it from activating the receptor complex, according to Corren and colleagues. TSLP is released in response to environmental and pro-inflammatory stimuli, and mediates type 2 immunity through activity on multiple cell types and up-regulation of cytokines by antigen-specific type 2 helper cells (Th2).

"These findings highlight the potential advantages of targeting an upstream cytokine such as TSLP, which may affect disease activity more broadly than inhibition of a single downstream pathway," the investigators wrote. "TSLP expression is higher in the airways of patients with asthma than in those of healthy controls, and its levels correlate with Th2 cytokine and chemokine expression and disease severity."

“That's the impression based on the phase 2b study, using the primary end point, which was exacerbations,” Corren said, explaining the evidence for this potential advantage to MD Magazine. “When you compare above and below 250 eosinophils (cells/µL), the drug performed very similarly in both of those subgroups of high and low eosinophils. If you look at other stratifiers, like exhaled nitric oxide (fractional, FeNO) or what we call the Th2 surrogate signature — which is a combination of IgE and blood eosinophils – again, for both the high and low stratifications, the drug seemed to have similar effect on reducing exacerbations."

The trial was conducted at 108 sites across 12 countries with patients whose asthma was not well controlled despite treatment with inhaled combination of long-acting beta-agonist (LABA) bronchodilator and fluticasone corticosteroid. Eligibility criteria included having at least 2 asthma exacerbations that required oral corticosteroid treatment or 1 severe exacerbation that required hospitalization in the year prior to trial entry, as well as meeting particular deficits in pulmonary function testing.

A total of 584 patients were randomized to receive tezepelumab, in 70-mg, 210-mg or 280-mg monthly doses, or placebo. The study primary efficacy endpoint was reduction in annualized rate of asthma exacerbations.

An exacerbation was defined as worsening of symptoms that required treatment with systemic corticosteroid, or an increased dose in those who had been receiving maintenance treatment, an emergency department visit with systemic corticosteroid treatment or inpatient hospitalization for worsened asthma symptoms.

The investigators reported that the annualized asthma exacerbation rates were 61% lower across tezepelumab groups than in those receiving placebo, irrespective of baseline blood eosinophil count or other indicators of Th2 status. The annualized rates at week 52 were 0.26, 0.19 and 0.22 in the low-dose, medium-dose, and high-dose tezepelumab groups, respectively, compared to 0.67 in the placebo group.

Time to first asthma exacerbation was longer across tezepelumab groups than with placebo, and risk for having any exacerbation was less. The investigators noted that treatment effect was observed as early as week 4, and was sustained throughout the 52-week study period.

"I think this may be the drug that, at least to date in the study we've done, looks like it may have efficacy in a non-Th2 population," Corren said. "But, we'll have to go through and study more patients to validate that."

The report of the phase 2 study of tezepelumab in adults with uncontrolled asthma was published September 7 in the New England Journal of Medicine.